The focus of this chapter is to provide the various production routes for radionuclides that have potential therapeutic qualities. Given the need for diagnostic pairing for many therapeutic radionuclides, production routes for several photo-emitting counterparts are also discussed. The goal of this chapter is to provide a summary of the physical, chemical and purity qualities including radiochemical, radionuclidic and specific/molar activities, for the proposed theranostic pairs, recognizing that in many cases compromises will have to be made. As of 2023, the vast majority of global diagnostic imaging is performed with 18F, 68Ga and 99mTc, all of which can be produced by cyclotrons or generators. There is no general approach to producing radionuclides for therapy. However, since most of these radionuclides are neutron-rich they are generally produced by neutron capture, fission, (ɣ,n) or via charged particle spallation of targets distant from the desired product. In the latter case, there will generally be a number of undesired radionuclidic impurities. Often these impurities cannot be removed through chemistry. The purification of mixed products has been achieved by passing the mixture through an on-line or off-line isotope separator. Details for these approaches will be considered.

This chapter describes the production and isolation methods for obtaining the radionuclides used in single photon emission computed tomography (SPECT). It presents the radionuclide with a description of how it is produced along with typical separation/purification approaches presently used. SPECT imaging is dominated by technetium-99m (99mTc), which accounts for more than 80% of all procedures. Thallium has a+1-oxidation state, making it a useful analog of potassium. It is used extensively in cardiac imaging even though there are 99mTc-tracers that deliver lower radiation exposure to the patient and can be prepared from generator-produced 99mTc. Like the photons from 99mTc, the gamma ray penetrates tissue very effectively without an excessive radiation dose. For this reason, it has, in many instances, replaced reactor-produced iodine-123.

Following a major shortage of 99Mo in the 2009–2010 period, concern grew that the aging reactor production facilities needed to be replaced. Most producers were using highly enriched 235U (HEU) as the target material. The Organisation for Economic Co-operation and Development and the International Atomic Energy Agency sought to remedy these issues by removing HEU from medical isotope production and implementing full cost recovery to enable new production entities to compete with the existing multipurpose reactor facilities, which were heavily subsidized by their respective governments. This review examines the various approaches to producing 99Mo and/or 99mTc with a critical eye toward their potential success in ( a) producing the medical isotopes and ( b) being able to successfully enter and compete in the market. Because many of the new approaches are adapting existing technologies for commercial businesses, some of the details are of a proprietary nature and not available for in-depth technical review.

Gas target systems are the main tool for producing [11C]CH4 or [11C]CO2 for nuclear medicine. Modelling has suggested that adsorption to the target body walls plays an important role in the recoverable radioactive yield from a target system. Here, we build on a previous model describing adsorption by including the kinetics of intermediary chemical species. The model equations are presented and simplified to a tractable form, from which expressions for the saturation yield and the initial production rate are derived. The model agrees with experimental data from different target body materials, beam currents, and loading pressures. The model predicts that increasing chemical kinetic rates will increase the recoverable yield from a target. This is experimentally validated with a forced convection target which increases in-target gas mixing, favoring reaction kinetics over adsorption losses.

A forced-convection gas target for the production of [11C]CH4 on a 13 MeV cyclotron was constructed and tested. A small fan was incorporated into the back of the target, which mixes the target gas during irradiation. The effect of the forced convection alone on the target operation and the [11C]CH4 yield was measured. Forced convection improved the target yield by up to 16 ± 4%. In addition, improvement in heat transfer of up to 70% was observed to be a function of fan speed. Operating with forced convection allowed delivery of 21% higher beam currents while still staying in the acceptable pressure rise during irradiation, providing a 25 ± 7% greater yield.

The development of alpha-emitting radiopharmaceuticals using 211At requires quantitative determination of the time-dependent nature of the 211At biodistribution. However, imaging-based methods for acquiring this information with 211At have not found wide-spread use because of its low abundance of decay emissions suitable for external detection. In this publication we demonstrate the theranostic abilities of the 211At/209At isotope pair and present the first-ever 209At SPECT images. The VECTor microSPECT/PET/CT scanner was used to image 209At with a collimator suitable for the 511 keV annihilation photons of PET isotopes. Data from distinct photopeaks of the 209At energy spectrum (195 keV (22.6%), 239 keV (12.4 %), 545 keV (91.0 %), a combined 782/790 keV peak (147 %), and 209Po x-rays (139.0 %)) were independently evaluated for use in image reconstructions using Monte Carlo (GATE) simulations and phantom studies. 209At-imaging in vivo was demonstrated in a healthy mouse injected with 10 MBq of free [209At]astatide. Image-based measurements of 209At uptake in organs of interest—acquired in 5 min intervals—were compared to ex vivo gamma counter measurements of the same organs. Simulated and measured data indicated that—due to the large amount of scatter from high energy (>750 keV) gammas—reconstructed images using the x-ray peak outperformed those obtained from other peaks in terms of image uniformity and spatial resolution, determined to be  <0.85 mm. 209At imaging using the x-ray peak revealed a biodistribution that matched the known distribution of free astatide, and in vivo image-based measurements of 209At uptake in organs of interest matched ex vivo measurements within 10%. We have acquired the first 209At SPECT images and demonstrated the ability of quantitative SPECT imaging with 209At to accurately determine astatine biodistributions with high spatial and temporal resolution.

BACKGROUND:Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease.METHODS:Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-11C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis.FINDINGS:We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age.INTERPRETATION:LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells.FUNDING:Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation.

Gas target systems have been used for decades on cyclotrons to produce radionuclides for medical imaging. However, the activity recovered from such targets is often lower than its theoretically predicted value. Past research has suggested that nuclide interactions with the walls of the target body may play a key role in the loss of recoverable radionuclide activity. Here, we consider gas targets and modify the standard radionuclide production equation by adding a loss term representing radionuclides depositing on the walls of the target. We derive the form of the deposition term based on a simple adsorption model which is then linearized by solving for leading order terms. The resulting production equation uses one fitting parameter to give an estimate of the recoverable activity produced in a target system, taking adsorption into account. The model is then fit to six data series, taken in-house and reported in the literature and a parity plot compares model predictions to experimental data. The model is able to better track the data than any previous models, and points towards a phenomenological understanding of adsorption in target systems.

Mass-separated francium beams (Fr-211 or Fr-213) were implanted into solid targets for producing Rn-211 (14.6 h half-life) or At-209 (5.41 h), in situ. Rn-211 was transferred to dodecane and isolated from contaminants, providing sources for At-211 (7.21 h) production by Rn-211 decay (73%). At-209 was recovered with high radionuclidic purity in aqueous solutions, directly. These experiments demonstrated Fr beam implantations as a novel method for producing preclinical quantities of Rn-211/(211) Fit (for therapy) and At-209 (for imaging).

Mass-separated francium beams (211Fr or 213Fr) were implanted into solid targets for producing 211Rn (14.6h half-life) or 209At (5.41h), in situ. 211Rn was transferred to dodecane and isolated from contaminants, providing sources for 211At (7.21h) production by 211Rn decay (73%). 209At was recovered with high radionuclidic purity in aqueous solutions, directly. These experiments demonstrated Fr beam implantations as a novel method for producing preclinical quantities of 211Rn/211At (for therapy) and 209At (for imaging).

The radionuclidic purity of cyclotron-produced Tc-99m has been measured by gamma ray spectroscopy and compared to the results of a quick release test modeled after the molybdenum breakthrough test performed on generator-derived Tc-99m. Excellent radionuclidic purity is reported for samples produced at BCCA during our clinical trial. The quick release test results agree well with the gamma ray analysis.

The purpose of this work is to introduce a universal mathematical model to explain a gas target behaviour at steady-state time scale. To obtain our final goal, an analytical model is proposed to study the pressure rise in the targets used to produce medical isotopes on low-energy cyclotrons. The model is developed based on the assumption that during irradiation the system reaches steady-state. The model is verified by various experiments performed at different beam currents, gas type, and initial pressures at 13 MeV cyclotron at TRIUMF. Excellent agreement is achieved.

Introduction: The availability of At-211 for targeted alpha therapy research can be increased by the Rn-211/At-211 generator system, whereby At-211 is produced by Rn-211 electron capture decay. This study demonstrated the feasibility of using generator-produced At-211 to label monoclonal antibody (BC8, anti-human CD45) for preclinical use, following isolation from the Po-207 contamination also produced by these generators (by Rn-211 a-decay).Methods: Rn-211 was produced by Fr-211 electron capture decay following mass separated ion beam implantation and chemically isolated in liquid alkane hydrocarbon (dodecane). 21 At HI produced by the resulting Rn-211 source was extracted in strong base (2 N NaOH) and purified by granular Te columns. BC8-810 (antibody conjugated with closo-decaborate(2-)) was labeled with generator-produced At-211 and purified by PD-10 columns.Results: Aqueous solutions extracted from the generator were found to contain At-211 and Po-207, isolated from Rn-211. High radionuclidic purity was obtained for At-211 eluted from Te columns, from which BC8-810 monoclonal antibody was successfully labeled. If not removed, Po-207 was found to significantly contaminate the final At-211-BC8-B10 product. High yield efficiencies (decay-corrected, n = 3) were achieved for 211At extraction from the generator (86% +/- 7%), Te column purification (70% +/- 10%), and antibody labeling (76% +/- 2%).Conclusions: The experimental Rn-211/(211) At. HE generator was shown to be well-suited for preclinical At-211-based research. Advances in knowledge: We believe that these experiments have furthered the knowledge-base for expanding accessibility to At-211 using the Rn-211/(211) At generator system. Implications for patient care: As established by this work, the Rn-211/(211) At generator has the capability of facilitating preclinical evaluations of At-211-based therapies. (C) 2017 Elsevier Inc. All rights reserved.

Attaching alpha-emitting radionuclides to cancer-targeting agents increases the anti-tumor effects of targeted cancer therapies. The success of alpha therapy for treating bone metastases has increased interest in using targeted alpha therapy (TAT) to treat a broad spectrum of metastatic cancers. Estimating radiation doses to targeted tumors, including small (u003c250 μm) clusters of cancer cells, and to non-targeted tissues is critical in the pre-clinical development of TATs. However, accurate quantification of heterogeneous distributions of alpha-emitters in small metastases is not possible with existing pre-clinical in-vivo imaging systems. Ex-vivo digital autoradiography using a scintillator in combination with an image intensifier and a charged coupled device (CCD) has gained interest for pre-clinical ex-vivo alpha particle imaging. We present a simulation-based analysis of the fundamental spatial resolution limits of digital autoradiography systems. Spatial resolution was quantified in terms of the modulation transfer function (MTF) and Wagneru0027s equivalent aperture. We modeled systems operating in either particle-counting (PC) or energy-integrating (EI) mode using a cascaded systems approach that accounts for: 1) the stopping power of alpha particles; 2) the distance alpha particles travel within the scintillator; 3) optical blur, and; 4) binning in detector elements. We applied our analysis to imaging of astatine-211 using an LYSO scintillator with thickness ranging from 10 μm to 20 μm. Our analysis demonstrates that when these systems are operated in particle-counting mode with a centroid-calculation algorithm, the effective apertures of ~35 μm can be achieved, which suggests that digital autoradiography may enable quantifying the uptake of alpha emitters in tumors consisting of a few cancer cells. Future work will investigate the image noise and energy-resolution properties of digital autoradiography systems.

INTRODUCTION:The availability of 211At for targeted alpha therapy research can be increased by the 211Rn/211At generator system, whereby 211At is produced by 211Rn electron capture decay. This study demonstrated the feasibility of using generator-produced 211At to label monoclonal antibody (BC8, anti-human CD45) for preclinical use, following isolation from the 207Po contamination also produced by these generators (by 211Rn α-decay).METHODS:211Rn was produced by 211Fr electron capture decay following mass separated ion beam implantation and chemically isolated in liquid alkane hydrocarbon (dodecane). 211At produced by the resulting 211Rn source was extracted in strong base (2N NaOH) and purified by granular Te columns. BC8-B10 (antibody conjugated with closo-decaborate(2-)) was labeled with generator-produced 211At and purified by PD-10 columns.RESULTS:Aqueous solutions extracted from the generator were found to contain 211At and 207Po, isolated from 211Rn. High radionuclidic purity was obtained for 211At eluted from Te columns, from which BC8-B10 monoclonal antibody was successfully labeled. If not removed, 207Po was found to significantly contaminate the final 211At-BC8-B10 product. High yield efficiencies (decay-corrected, n=3) were achieved for 211At extraction from the generator (86%±7%), Te column purification (70%±10%), and antibody labeling (76%±2%).CONCLUSIONS:The experimental 211Rn/211At generator was shown to be well-suited for preclinical 211At-based research.ADVANCES IN KNOWLEDGE:We believe that these experiments have furthered the knowledge-base for expanding accessibility to 211At using the 211Rn/211At generator system.IMPLICATIONS FOR PATIENT CARE:As established by this work, the 211Rn/211At generator has the capability of facilitating preclinical evaluations of 211At-based therapies.

TRIUMF has a long history of medical isotope production. For more than 40 years, the Life Sciences Division at TRIUMF has produced isotopes for Positron Emission Tomography (PET) for the local hospitals. Recently, the division has taken on the challenge to expand the facility's isotope repertoire to isotopes for imaging to treatment. At the smallest cyclotron at TRIUMF with energy of 13 MeV, radiometals are being produced in a liquid target which is typically used for PET isotope production. This effort makes radiometals available for early stage research and preclinical trials. At beam energy of 24 MeV, we produce 99mTc from 100Mo with a cyclotron, the most common isotope for Single-Photon-Emission-Computed-Tomography (SPECT) and the most common isotope for nuclear imaging. The use of a cyclotron bypasses the common production route via a nuclear reactor as well as enriched uranium. And finally, at our 500 MeV cyclotron we have demonstrated the production of α emitters useful for targeted alpha therapy. Herein, these efforts are summarized.

1873 Objectives Cyclotron-produced 99mTc (CPTc) is an attractive alternative production method for this important medical isotope. Proton irradiation of 100Mo targets containing small amounts of 94-98Mo leads to the production of very small quantities of radioactive technetium isotopes other than 99mTc (Tc-impurities). These impurities contribute to patient dose and may potentially affect image quality. Studies of dose increases (DIs) due to impurities in CPTc, as obtained from different targets, irradiation and injection parameters, allowed us to create dose-based limits for these parameters leading to clinically acceptable samples. However, image quality was not considered in these studies. The aim of the present work is to provide a comprehensive analysis of the effects of Tc impurities in the CPTc samples on image quality in order to allow production sites to avoid delivering CPTc that will affect image quality in clinical studies. This will lead to new image-based CPTc production limits. Only those samples which meet both dose and image limits should be used in clinical procedures. Methods Both Monte-Carlo simulation (GATE v6.1) and phantom experiments (planar and tomographic) were used in this study. Production conditions included two proton beam energies (18 and 24 MeV), a range of image acquisition times (2-24 hours after the end of beam (EOB)) and five different target compositions. The image spatial resolution, defined by the full width at half-maximum (FWHM) of the point spread function, and the modulation transfer function (MTF) of the imaging system, were studied using simulated point sources placed in air and in water. Image contrast and background from scattered high-energy photons were evaluated (in simulations and experiments) using a water filled Jaszczak phantom containing two bottles and six spheres filled with activity. These parameters were analyzed for the region in close proximity to all the inserts, where potential contributions from scattered photons were highest. Image-based effects based on production conditions and acquisition times were compared with dose-based limits established in a previous study (Phys Med Biol 57(6):1499-515). Results For each target, the quality of images obtained from CPTc produced at 24 MeV was more affected than CPTc produced at 18 MeV. For scans performed within 24h after EOB using CPTc samples obtained from the targets containing 99.82% and 99.54% of 100Mo irradiated with 18 and 24 MeV beams, and for target containing 97.39% of 100Mo irradiated with 18 MeV beams, there was no noticeable difference in image resolution (FWHM) and MTF between CPTc and pure 99mTc. For targets with higher 94-97Mo contents, the CPTc FWHM was higher than that of pure 99mTc by up to 15% at 24h after EOB, and MTF showed a higher scatter component which was increasing with time. The image contrast for the two best targets (99.82% and 99.54% of 100Mo) decreased by 5% (relative to pure 99mTc) for 18 MeV CPTc, and by 20% for 24 MeV CPTc, when imaging was performed at 24h after EOB. However, contrast decreased by up to 70% for other targets. Only slight FWHM increase was found for CPTc samples for which patient DIs were Conclusions Image quality remains unaffected for CPTc samples produced with target compositions that minimize 94-97Mo contamination. For targets with higher 94-97Mo contents, high-energy scattered photons originating from produced Tc impurities degrade image quality. This is more pronounced at higher energy irradiations and in later acquisitions. These findings are consistent with the production conditions determined based on dosimetry considerations (Phys Med Biol 57(6):1499-515). $$table_{A0DDD980-7100-497B-8279-243073F8BDD6}$$